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Alemtuzumab

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MEDICATION SAFETY ISSUES
High alert medication: The Institute for Safe Medication Practices (ISMP) includes this medication among its list of drug classes which have a heightened risk of causing significant patient harm when used in error.

SPECIAL ALERTS
Alemtuzumab: Reports of Infection-Related Fatalities – November 2008

Bayer HealthCare and Genzyme, in conjunction with Health Canada, have issued notice to Canadian hospitals concerning reports of infection-related fatalities in patients receiving consolidation therapy with MabCampath® (alemtuzumab). Preliminary safety data from the ongoing phase II U.S. clinical trial CALGB10101 has reported fatalities in 6 out of 51 patients with B-cell chronic lymphocytic leukemia (B-CLL) receiving fludarabine and rituximab induction therapy followed by alemtuzumab therapy for remission consolidation.

Fatal infections included viral meningitis, Listeria meningitis, Legionella pneumonia, cytomegalovirus (CMV), Pneumocystis jiroveci pneumonia (PCP), and Epstein-Barr virus (EBV) associated lymphoproliferative disorder.

The potential contributory role of any of the three chemotherapeutic agents is not clear based on available data. The infectious complications may have resulted from prolonged immunosuppression. An additional noninfection-related fatality, thought to be transfusion-associated graft-versus-host disease (TAGVHD), has also been reported.

Use of alemtuzumab as consolidation therapy is presently not approved in Canada. An updated product monograph including this new important safety information is forthcoming. Further information can be found at http://www.hc-sc.gc.ca/dhp-mps/medeff/advisories-avis/prof/_2008/mabcampath_nth-aah-eng.php

U.S. BRAND NAMES — Campath®

PHARMACOLOGIC CATEGORY
Antineoplastic Agent, Monoclonal Antibody

DOSING: ADULTS — Note: Dose escalation is required; usually accomplished in 3-7 days. Single doses >30 mg or cumulative doses >90 mg/week increase the incidence of pancytopenia. Pretreatment (with acetaminophen and diphenhydramine) is recommended prior to the first dose, with dose escalations, and as clinically indicated; I.V. hydrocortisone may be used for severe infusion-related reactions. Reinitiate with gradual dose escalation if treatment is withheld ≥ 7 days.

B-cell CLL:
I.V. infusion: Initial: 3 mg/day beginning on day 1; if tolerated (infusion reaction ≤ grade 2), increase to 10 mg/day; if tolerated (infusion reaction ≤ grade 2), increase to maintenance of 30 mg/dose 3 times/week on alternate days for a total duration of therapy of up to 12 weeks
SubQ (unlabeled route): Initial: 3 mg on day 1; if tolerated 10 mg on day 3; if tolerated increase to 30 mg on day 5; maintenance: 30 mg/dose 3 times/week for a maximum of 18 weeks (Lundin, 2002) or 3 mg on day 1; if tolerated 10 mg on day 2; if tolerated 30 mg on day 3, followed by 30 mg/dose 3 times/week for 4-12 weeks (Stilgenbauer, 2009)

Cutaneous T-cell lymphoma (unlabeled use): I.V. infusion: 3 mg on day 1; if tolerated increase the next dose to 10 mg; if tolerated increase the next dose to 30 mg; Maintenance dose: 30 mg/dose 3 times/week for up to 12 weeks (Lundin, 2003)

Peripheral T-cell lymphoma (unlabeled use):I.V. infusion: 3 mg on day 1; 10 mg on day 3, followed by 30 mg/dose 3 times/week for a duration of therapy of up to 12 weeks (Enblad, 2004)

T-cell prolymphocytic leukemia (unlabeled use):I.V. infusion: Initial test dose 3 mg or 10 mg, followed by dose escalation to 30 mg/dose 3 times/week as tolerated (Dearden, 2001)
or
Week 1: 3 mg on day 1; 10 mg on day 2; 30 mg on day 3, followed in subsequent weeks by 30 mg/dose on alternate days 3 times/week for a total of 4-12 weeks (Ferrajoli, 2003)
or
Initial dose: 3 mg day 1, if tolerated increase to 10 mg day 2, if tolerated increase to 30 mg on day 3 (days 1, 2, and 3 are consecutive days), followed by 30 mg/dose every Monday, Wednesday, Friday for a total of 4-12 weeks (Keating, 2002)

DOSING: ELDERLY — Refer to adult dosing.

DOSING: ADJUSTMENT FOR TOXICITY
Dosage adjustment for nonhematologic toxicity:
Grade 3 or 4 infusion reaction: Withhold infusion.
Serious infection or other serious adverse reaction: Withhold alemtuzumab until resolution.
Autoimmune anemia or autoimmune thrombocytopenia: Discontinue alemtuzumab.

Dosage adjustment for hematologic toxicity (severe neutropenia or thrombocytopenia, not autoimmune):
First occurrence: ANC <250/µL and/or platelet count ≤ 25,000/µL: Hold therapy; resume at 30 mg/dose when ANC ≥ 500/µL and platelet count ≥ 50,000/µL.
Second occurrence: ANC <250/µL and/or platelet count ≤ 25,000/µL: Hold therapy; resume at 10 mg/dose when ANC ≥ 500/µL and platelet count ≥ 50,000/µL.
Third occurrence: ANC <250/µL and/or platelet count ≤ 25,000/µL: Discontinue alemtuzumab.
Patients with a baseline ANC ≤ 250/µL and/or a baseline platelet count ≤ 25,000/µL at initiation of therapy: If ANC and/or platelet counts decrease to ≤ 50% of the baseline value, hold therapy.
First occurrence: When ANC and/or platelet count return to baseline, resume therapy at 30 mg/dose.
Second occurrence: When ANC and/or platelet count return to baseline, resume therapy at 10 mg/dose.
Third occurrence: Discontinue alemtuzumab.

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DOSAGE FORMS — Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Injection, solution [preservative free]:
Campath®: 30 mg/mL (1 mL) [contains polysorbate 80; disodium edetate]

DOSAGE FORMS: CONCISE
Injection, solution [preservative free]:
Campath®: 30 mg/mL (1 mL)

GENERIC EQUIVALENT AVAILABLE — No

ADMINISTRATION — Administer by I.V. infusion over 2 hours. Consider premedicating with diphenhydramine 50 mg and acetaminophen 500-1000 mg 30 minutes before initiation of infusion. Hydrocortisone 200 mg has been effective in decreasing severe infusion-related events. Start anti-infective prophylaxis. Other drugs should not be added to or simultaneously infused through the same I.V. line. Do not give I.V. push.

SubQ (unlabeled route): SubQ administration has been studied (Lundin, 2002; Stilgenbauer, 2009); an increased rate of injection site reactions has been observed, with only rare incidences of chills or infusion-like reactions typically observed with I.V. infusion. A longer dose escalation time (1-2 weeks) may be needed due to injection site reactions (Lundin, 2002). Premedication and anti-infective prophylaxis regimens should be given as are recommended with I.V. administration.

COMPATIBILITY — Stable in D5W, NS. Medications should not be added to the solution or simultaneously infused through the same I.V. line.

USE — Treatment of B-cell chronic lymphocytic leukemia (B-CLL)

USE – UNLABELED / INVESTIGATIONAL — Treatment of cutaneous T-cell lymphoma, peripheral T-cell lymphoma, refractory T-cell prolymphocytic leukemia, refractory or resistant autoimmune cytopenias; preconditioning regimen and prophylaxis of graft-versus-host disease (GVHD) in allogeneic stem cell transplant; immunosuppressant in solid organ transplant (induction and rejection)

ADVERSE REACTIONS SIGNIFICANT
>10%:
Cardiovascular: Hypotension (15% to 32%), peripheral edema (13%), hypertension (11% to 15%), dysrhythmia/tachycardia/SVT (10% to 14%)
Central nervous system: Fever (69% to 85%), chills (53%), fatigue (22% to 34%), headache (13% to 24%), dysthesias (15%), dizziness (12%)
Dermatologic: Rash (13% to 40%), urticaria (16% to 30%), pruritus (14% to 24%)
Gastrointestinal: Nausea (47% to 54%), vomiting (33% to 41%), anorexia (20%), diarrhea (10% to 22%), stomatitis/mucositis (14%), abdominal pain (11%)
Hematologic: Lymphopenia (grades 3/4: 97%), neutrope
nia (77% to 85%; grade 3/4: 42% to 70% [median onset: 31 days, median duration: 28-37 days]), anemia (76% to 80%; grade 3/4: 12% to 47% [median onset: 31 days, median duration 8 days]), thrombocytopenia (71% to 72%; grade 3/4: 13% to 52% [median onset: 9 days; median duration: 14-21 days])
Local: Injection site reaction (SubQ administration: 90%)
Neuromuscular & skeletal: Rigors (86% to 89%), skeletal pain (24%), weakness (13%), myalgia (11%)
Respiratory: Dyspnea (14% to 26%), cough (25%), bronchitis/pneumonitis (21%), pneumonia (16%), pharyngitis (12%)
Miscellaneous: Infection (43% to 74%; grades 3/4: 21% to 37%; incidence is lower if prophylactic anti-infectives are utilized), CMV viremia (55%), infusion reactions (grades 3/4: 10% to 35%), diaphoresis (19%), CMV infection (6% to 16%), sepsis (15%; grades 3/4: 3% to 10%), herpes viral infections (1% to 11%)

1% to 10%:
Cardiovascular: Chest pain (10%)
Central nervous system: Insomnia (10%), malaise (9%), anxiety (8%), depression (7%), temperature change sensation (5%), somnolence (5%)
Dermatologic: Purpura (8%), erythema (4%)
Gastrointestinal: Dyspepsia (10%), constipation (9%)
Hematologic: Neutropenic fever (10%; grades 3/4: 5% to 10%), pancytopenia/marrow hypoplasia (5% to 6%; grade 3/4: 3%), positive Coombs’ test without hemolysis (2%), autoimmune thrombocytopenia (2%), autoimmune hemolytic anemia (1%)
Neuromuscular & skeletal: Back pain (10%), tremor (3% to 7%)
Respiratory: Bronchospasm (9%), epistaxis (7%), rhinitis (7%)
Miscellaneous: Moniliasis (8%)

<1% (Limited to important or life-threatening): Acidosis, acute renal failure, acute respiratory distress syndrome, agranulocytosis, alkaline phosphatase increased, allergic reactions, anaphylactoid reactions, angina pectoris, angioedema, anuria, aphasia, aplastic anemia, arrhythmia, ascites, asthma, atrial fibrillation, bacterial infection, biliary pain, bone marrow aplasia, bullous eruption, capillary fragility, cardiac arrest, cardiac failure, cardiac insufficiency, cardiomyopathy, cellulitis, cerebral hemorrhage, cerebrovascular disorder, chronic inflammatory demyelinating polyradiculoneuropathy (CIDP), coagulation abnormality, colitis, coma, COPD, coronary artery disorder, cyanosis, deep vein thrombosis, dehydration, diabetes mellitus exacerbation, disseminated intravascular coagulation (DIC), duodenal ulcer, ejection fraction decreased, endophthalmitis, Epstein-Barr virus associated lymphoproliferative disorder, esophagitis, fluid overload, flu-like syndrome, gastrointestinal hemorrhage, Goodpasture's syndrome, Graves' disease, Guillain-Barre syndrome, hallucinations, hematemesis, hematoma, hematuria, hemolysis, hemolytic anemia, hemoptysis, hepatic failure, hepatocellular damage, HF, hyperbilirubinemia, hyper-/hypoglycemia, hyper-/hypokalemia, hypersensitivity, hyperthyroidism, hypoalbuminemia, hyponatremia, hypovolemia, hypoxia, idiopathic thrombocytopenic purpura (ITP), interstitial pneumonitis, intestinal obstruction, intestinal perforation, intracranial hemorrhage, Legionella pneumonia, Listeria meningitis, lymphadenopathy, marrow depression, melena, MI, mouth edema, myositis, optic neuropathy, osteomyelitis, pancreatitis, paralysis, paralytic ileus, paroxysmal nocturnal hemoglobinuria-like monocytes, peptic ulcer, pericarditis, peritonitis, plasma cell dyscrasia, phlebitis, pleural effusion, pleurisy, Pneumocystis jiroveci pneumonia, pneumothorax, polymyositis, progressive multifocal leukoencephalopathy, pseudomembranous colitis, pulmonary edema, pulmonary embolism, pulmonary fibrosis, pulmonary infiltration, pure red cell aplasia, purpuric rash, renal dysfunction, respiratory alkalosis, respiratory arrest, respiratory depression, respiratory insufficiency, seizure (grand mal), serum sickness, sinus bradycardia, splenic infarction, splenomegaly, stridor, subarachnoid hemorrhage, syncope, toxic nephropathy, thrombocythemia, thrombophlebitis, throat tightness, transfusion-associated GVHD, tuberculosis, tumor lysis syndrome, ureteric obstruction, urinary retention, urinary tract infection, ventricular arrhythmia, ventricular tachycardia, viral meningitis, virus reactivation (latent)

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CONTRAINDICATIONS — There are no contraindications listed in the manufacturer’s labeling WARNINGS / PRECAUTIONS
Boxed warnings: Hematologic toxicity: See “Concerns related to adverse effects” below. Infections: See “Concerns related to adverse effects” below. Infusion reactions: See “Concerns related to adverse effects” below.

Special handling: Hazardous agent: Use appropriate precautions for handling and disposal.

Concerns related to adverse effects: Hematologic toxicity: [U.S. Boxed Warning]: Serious and fatal cytopenias (including pancytopenia, bone marrow hypoplasia, autoimmune hemolytic anemia, and autoimmune idiopathic thrombocytopenia) have occurred. Single doses >30 mg or cumulative weekly doses >90 mg are associated with an increased incidence of pancytopenia. Severe prolonged myelosuppression, hemolytic anemia, pure red cell aplasia, and bone marrow aplasia have also been reported. Discontinue therapy during serious hematologic or other serious toxicity (except lymphopenia) until the event resolves. Permanently discontinue if autoimmune anemia or autoimmune thrombocytopenia occurs. Patients receiving blood products should only receive irradiated blood products due to the potential for transfusion-associated GVHD during lymphopenia. Infections: [U.S. Boxed Warning]: Serious and potentially fatal infections (bacterial, viral, fungal, and protozoan) have been reported. Prophylactic medications against PCP pneumonia and herpes viral infections are recommended upon initiation of therapy and for at least 2 months following last dose or until CD4+ counts are ≥ 200 cells/µL (whichever is later). Severe and prolonged lymphopenia may occur; CD4+ counts usually return to ≥ 200 cells/µL within 2-6 months; however, CD4+ and CD8+ lymphocyte counts may not return to baseline levels for more than 1 year. Withhold treatment during serious infections; may be reinitiated upon resolution of infection. Monitor for CMV infection (during and for at least 2 months after completion of therapy); initiate appropriate antiviral treatment and withhold alemtuzumab for CMV infection or confirmed CMV viremia (withhold alemtuzumab during CMV antiviral treatment). Infusion reactions: [U.S. Boxed Warning]: Serious and potentially fatal infusion-related reactions may occur; withhold treatment for grade 3 or 4 infusion reactions. Gradual escalation to the recommended maintenance dose is required at initiation and with therapy interruption (for ≥ 7 days) to minimize infusion-related reactions. Infusion reaction symptoms may include acute respiratory distress syndrome, anaphylactic shock, angioedema, bronchospasm, cardiac arrest, cardiac arrhythmias, chills, dyspnea, fever, hypotension, myocardial infarction, pulmonary infiltrates, rash, rigors, syncope, or urticaria. The incidence of infusion reaction is highest during the first week of treatment. Premedication with acetaminophen and an oral antihistamine is recommended. Medications for the treatment of reactions should be available for immediate use. Use caution and carefully monitor blood pressure in patients with ischemic heart disease and patients on antihypertensive therapy. Reinitiate with gradual dose escalation if treatment is withheld ≥ 7 days.

Special populations: Men of reproductive potential: Should use effective contraceptive methods during treatment and for a minimum of 6 months following therapy. Pediatrics: Safety and efficacy have not been established in children. Women of childbearing potential: Should use effective contraceptive methods during treatment and for a minimum of 6 months following therapy.

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Other warnings/precautions: Immunizations: Patients should not be immunized with live, viral vaccines during or recently after treatment. The ability to respond to any vaccine following therapy is unknown.

DRUG INTERACTIONS
Abciximab: May enhance the potential for allergic or hypersensitivity reactions to Monoclonal Antibodies. Also may cause thrombocytopenia or diminished therapeutic effects. Risk C: Monitor therapy

Echinacea: May diminish the therapeutic effect of Immunosuppressants. Risk D: Consider therapy modification

Leflunomide: Immunosuppressants may enhance the adverse/toxic effect of Leflunomide. Specifically, the risk for hematologic toxicity such as pancytopenia, agranulocytosis, and/or thrombocytopenia may be increased. Management: Consider not using a leflunomide loading dose in patients receiving other immunosuppressants. Patients receiving both leflunomide and another immunosuppressant should be monitored for bone marrow suppression at least monthly. Risk D: Consider therapy modification

Natalizumab: Immunosuppressants may enhance the adverse/toxic effect of Natalizumab. Specifically, the risk of concurrent infection may be increased. Risk X: Avoid combination

Trastuzumab: May enhance the neutropenic effect of Immunosuppressants. Risk C: Monitor therapy

Vaccines (Inactivated): Immunosuppressants may diminish the therapeutic effect of Vaccines (Inactivated). Risk C: Monitor therapy

Vaccines (Live): Immunosuppressants may enhance the adverse/toxic effect of Vaccines (Live). Vaccinial infections may develop. Immunosuppressants may diminish the therapeutic effect of Vaccines (Live). Risk X: Avoid combination

ETHANOL / NUTRITION / HERB INTERACTIONS — Herb/Nutraceutical: Echinacea may diminish the therapeutic effect of alemtuzumab.

PREGNANCY RISK FACTOR — C (show table)

PREGNANCY IMPLICATIONS — Human IgG is known to cross the placental barrier; therefore, alemtuzumab may also cross the barrier and cause fetal B- and T-lymphocyte depletion. Well-controlled human trials have not been done. Use during pregnancy only if the benefit to the mother outweighs the potential risk to the fetus. Effective contraception is recommended during and for 6 months after treatment for women of childbearing potential and men of reproductive potential.

LACTATION — Excretion in breast milk unknown/not recommended

BREAST-FEEDING CONSIDERATIONS — Human IgG is excreted in breast milk; therefore, alemtuzumab may also be excreted in milk. Breast-feeding should be discontinued during treatment and for at least 3 months following the last dose.

PRICING — (data from drugstore.com)
Solution (Campath)
30 mg/mL (3): $5999.53

MONITORING PARAMETERS — Vital signs; carefully monitor BP especially in patient with ischemic heart disease or on antihypertensive medications; CBC with differential and platelets (weekly, more frequent if worsening); signs and symptoms of infection; CD4+ lymphocyte counts (after treatment until recovery); CMV antigen (every 1-2 weeks). Monitor closely for infusion reactions (including hypotension, rigors, fever, shortness of breath, bronchospasm, chills, and/or rash).

CANADIAN BRAND NAMES — MabCampath®

INTERNATIONAL BRAND NAMES — Campath (AR, PE, UY); MabCampath (AT, AU, BE, BG, CH, CO, CZ, DE, DK, ES, FI, FR, GB, GR, HK, HN, ID, IE, IL, IT, KP, MY, NL, NO, PT, RU, SE, SG, TR, ZA); Mabcampath (PL)

MECHANISM OF ACTION — Binds to CD52, a nonmodulating antigen present on the surface of B and T lymphocytes, a majority of monocytes, macrophages, NK cells, and a subpopulation of granulocytes. After binding to CD52+ cells, an antibody-dependent lysis of leukemic cells occurs.

PHARMACODYNAMICS / KINETICS
Distribution: Vd: I.V.: 0.1-0.4 L/kg

Metabolism: Clearance decreases with repeated dosing (due to loss of CD52 receptors in periphery), resulting in a sevenfold increase in AUC.

Half-life elimination: I.V.: 11 hours (following first 30 mg dose; range: 2-32 hours); 6 days (following the last 30 mg dose; range: 1-14 days)

PATIENT INFORMATION — You will need frequent laboratory tests during course of therapy. Do not use any prescription or OTC medications unless approved by your prescriber. Maintain adequate hydration (2-3 L/day unless otherwise instructed) and nutrition (frequent small meals will help). You may experience abdominal pain, mouth sores, nausea, or vomiting (small frequent meals, good mouth care with soft toothbrush or swabs, sucking lozenges or chewing gum, and avoidance of spicy or salty foods may help). Report unresolved gastrointestinal problems, persistent fever, chills, muscle pain, skin rash, unusual bleeding or bruising, signs of infection (mouth sores, sore throat, white plaques in mouth or perianal area, burning on urination); swelling of extremities; difficulty breathing; chest pain or palpitations; or other persistent adverse reactions.

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